Stiff‐person syndrome revealing an occult gray zone lymphoma: A diagnostic challenge

Key Clinical Message Stiff‐Person Syndrome (SPS) can be associated with various malignancies, including lymphomas. Therefore, clinicians should always remain vigilant for the presence of an underlying malignancy, especially in older patients presenting with SPS. Abstract Stiff‐person syndrome (SPS) is a rare neurological disorder characterized by painful muscle spasms. It can occur as a paraneoplastic syndrome associated with various malignancies. We present a case of an older male adult with a history of recurrent fever episodes and elevated inflammatory markers for 1 year who subsequently developed neurological symptoms. The presence of positive amphiphysin antibodies led to the diagnosis of SPS, which prompted further investigations revealing an underlying Gray Zone lymphoma (GZL). This case highlights the challenges in diagnosing lymphoma and emphasizes the importance of considering SPS as a paraneoplastic syndrome in guiding toward the final diagnosis. The diagnostic challenge in our case is summarized in Chart 1.

of painful muscle spasms in his lower limbs.The patient had a history of recurrent, episodic fevers.Routine clinical and laboratory tests were performed, but no infectious or oncologic results were found.Subsequently, further pathologic tests were conducted to investigate the causes of SPS, which led to evidence of gray zone lymphoma (GZL).

| CASE PRESENTATION
A 66-year-old educated male is presented to the emergency department with painful muscle spasms in his lower limbs that have been occurring for a few days.He initially experienced difficulty walking and episodic limb pain, and he noticed a slowness in his movements a month ago.Additionally, he complained of a lack of concentration and memory loss over the past week.He had no history of trauma, loss of consciousness, headache, or vomiting.He had no history of surgery, allergies, addiction, or smoking.
However, he had a history of anemia, which was initially diagnosed as iron deficiency anemia.His evaluations did not reveal any evidence of gastrointestinal malignancies, and he has been treated with daily ferrous sulfate tablets.Furthermore, over the past year, he experienced recurrent episodes of weakness and fever with an almost 12-kg weight loss, leading to referrals to an infectious disease specialist.During these periods, he underwent evaluations for oncologic and infectious diseases, but no specific final diagnosis was reached.As a result, he was hospitalized multiple times and received treatment with intravenous antibiotics and corticosteroids.His medical files include investigations from his prior referral to hospital.These investigations are summarized in the next chapter.
Upon admission, his general condition was poor; he was confused and did not demonstrate signs of orientation to time and person.His vital signs were within the normal range.In his general examinations, there was no indication of icterus, cyanosis, lymphadenopathy, edema, or clubbing.However, severe conjunctival pallor is observed.On neurologic examinations, his coordination and sensation were normal.Cranial nerve examinations revealed normal results, except for signs of vertical gaze impairment.Higher mental function examinations indicated severe encephalopathy, with a Mini-Mental State Examination (MMSE) score of 18. Motor examinations showed normal muscle bulk and power (force = 5/5) in both upper and lower limbs, while bilaterally increased tone was observed in both the upper and lower limbs.His gate examinations revealed severe bradykinesia with a spastic gate.No other abnormal movement was observed.His plantar reflex examination showed an upward response.Other neurological examinations were normal.

| INVESTIGATIONS
As previously mentioned, the patient has undergone multiple referrals to oncologists and infectious disease specialists due to recurrent episodes of fever over the past year.These evaluations were conducted prior to referral to the neurologist.The patient's medical records include investigations from 3 months ago, when he was admitted to the hospital due to fever.These investigations are summarized in Table 1.
The abdomino-pelvic ultrasound study revealed normal results.The chest computed tomography (CT) scan showed mild consolidations in the inferior-posterior lobes of both lungs but was otherwise unremarkable.Subsequently, an endoscopy was performed, which indicated mild chronic erosive gastritis without intestinal metaplasia, peptic ulcer, or Helicobacter pylori infection.The colonoscopy study yielded normal findings.
The investigations concluded with a bone marrow aspiration and biopsy, which revealed a normocellular marrow with trilineage hematopoiesis and progressive maturation.The presence of plasma cells was noted at a level of 5%-7%.
Following these investigations, the patient's symptoms improved with the administration of intravenous antibiotics and corticosteroids, leading to his discharge from the hospital with the patient's informed consent.Unfortunately, the patient did not show up for further follow-up.His symptoms eventually progressed to neurologic deterioration, prompting him to seek medical attention at the emergency department.He presented with painful spasms and signs of severe encephalopathy.
Upon referral to the neurologist in the latest admission, a thorough neurological evaluation was done for the patient.His general laboratory findings were consistent with previously mentioned results, except for a lower hemoglobin level (7.6 mg/dL).Further investigations included a lumbar puncture, Immunologic tests, and paraneoplastic panel.These are summarized in Table 2.
Brain magnetic resonance imaging (MRI) did not reveal any abnormalities.However, a whole spine MRI study was conducted, which indicated moderate canal stenosis with pressure effect at the L5-S1 level.This finding could potentially explain the upward plantar reflex observed in the patient, although a more complex diagnosis was anticipated in this case.
Electroencephalography (EEG) results demonstrated a transient slowing pattern and some epileptic discharges.
The paraneoplastic panel study revealed an increase in amphiphysin antigen, which supported a diagnosis of SPS.To further investigate the underlying cause of SPS, an autoimmune encephalitis panel was conducted, including testing for GABAB receptor and anti-glutamate receptor antibodies.However, these tests yielded negative results.
Given the negative autoimmune encephalitis panel findings, attention was directed toward paraneoplastic etiologies of SPS, especially considering the patient's significant weight loss.A breast ultrasound study was performed, which showed normal results.Additionally, a whole-body bone scan indicated areas of focal uptake at the left fifth and tenth ribs.These findings were considered nonspecific and could potentially be attributed to either fractures or metastasis.
Despite the previous chest CT scan, a second highresolution CT (HRCT) of the chest was conducted.The HRCT report revealed a soft tissue density measuring 48 × 21 mm in the subcarinal space, along with several lymphadenopathies with a maximum short-axis diameter of 14 mm, which is depicted in Figure 1.Additionally, a thin rim of pleural effusion was observed on the right side, accompanied by mild atelectasis at the base of both lungs.
To further investigate the possibility of malignancy, bronchoalveolar lavage (BAL) cytology was performed.However, the results of the BAL cytology did not indicate the presence of malignant cells.
A needle biopsy of the mediastinal lymph node was performed and sent for microscopic examination.However, the specimen was deemed inadequate to definitively rule in or rule out lymphoproliferative disorders.The report indicated a polytypic lymphoid cell population with some anthracotic pigments present.Given the high clinical suspicion, the specimen was sent to another laboratory for a second review, along with immunohistochemistry (IHC) studies.
Histopathologic features of core needle biopsy show tiny fragments of lymphoid tissue with anthracosis, containing polymorphic lymphoid cells composed of small lymphocytes with few large atypical lymphoid cells resembling Hodgkin cell and Red-Sternberg cells in between (Figures 2 and 3).On IHC staining, the background small lymphocytes are positive for CD3 (Figure 4), and the mentioned large atypical cells are positive for CD30 (Figure 5), PAX5 (Figure 6), and CD20 (Figure 7).They show negative staining for CD15.Based on the morphological and IHC findings, the diagnosis of GZL was favored.

| DIFFERENTIAL DIAGNOSIS
Due to the warning signs in this patient (an older adult with fever and weight loss), the possibility of a malignancy was high.As previously mentioned, previous investigations were done to rule out possible malignancies including gastrointestinal malignancies, breast cancer, lung cancer, leukemia, lymphoma, and multiple myeloma.However, these investigations were all negative.Upon his referral to neurologist with painful muscle spasm, severe encephalopathy, and fever, several potential diagnoses were considered, including meningoencephalitis, neuroleptic malignant syndrome (NMS), parkinsonian disorders, progressive supranuclear palsy (PSP), and paraneoplastic syndromes.
However, among these diagnoses, paraneoplastic syndromes were more possible due to the phenotype of SPS, high clinical suspicion for a malignancy, and positive amphiphysin antigen.

| TREATMENT
As EEG results demonstrated epileptic discharges, levetiracetam at a dosage of 500 mg twice a day was started.Furthermore, given the patient's painful spasms, treatment was initiated with oral Baclofen at a dosage of 5 mg The strong clinical suspicion of paraneoplastic syndrome was supported by the previously introduced paraneoplastic syndrome care score. 5The patient exhibited the SPS phenotype and tested positive for amphiphysin antibody without a diagnosed cancer after less than 2 years of follow-up, achieving a score of 6 out of 8 points.This indicates a probable diagnosis of paraneoplastic syndrome.Consequently, treatment with intravenous immunoglobulin (IVIG) therapy was initiated at a dosage of 0.4 g/kg per day for 5 days following the detection of amphiphysin antibody results. 6,7However, since there was also a high clinical suspicion of malignancies, corticosteroid treatment was not initiated.These treatments were accompanied by a series of neurological evaluations aimed at reaching a definitive diagnosis.

| OUTCOME
Signs and symptoms of SPS subsided following treatment with Baclofen and Clobazam.The patient did not experience seizure, despite having epileptic discharges in the EEG results.Furthermore, the patient's cognition improved after treatment with IVIG, and the MMSE score increased to 25.
However, due to the lengthy process involved in obtaining a conclusive diagnosis and the rapid progression of the disease, the patient's condition deteriorated further.Tragically, the patient succumbed to the illness before treatment for the malignancy could be commenced.

| DISCUSSION
Stiff-person syndrome is an uncommon neurological autoimmune syndrome, with an incidence rate of one case per million. 1This syndrome can be categorized into three subgroups based on its etiology: autoimmune, paraneoplastic, and cryptogenic.Paraneoplastic SPS presents with a broad range of clinical manifestations, including weakness, seizures, gait abnormalities, diplopia, and myoclonus. 8Other paraneoplastic syndromes that share similarities with SPS include Opsoclonus myoclonus syndrome and progressive encephalomyelitis with rigidity and myoclonus. 8he diagnostic criteria for SPS, which have gained widespread acceptance, were revised by Dalakas  paraclinical indicators. 9In our case, we observed older male adult presenting with painful muscle spasms, positive serology for anti-amphiphysin autoantibodies, a positive clinical response to benzodiazepines, and the absence of any other neurological diagnosis that could account for his signs and symptoms.As a result, this case meets four out of the six criteria established by Dalakas et al. 9 Based on research findings, it has been determined that approximately 5% of SPS cases are paraneoplastic, and these cases are often linked to breast cancer or small-cell lung cancer. 10Nevertheless, there have been documented cases of SPS associated with Hodgkin lymphoma. 8To the best of our knowledge, there have been no reported instances of coexisting SPS and GZL.
Notably, the majority of case reports regarding paraneoplastic SPS focus on patients who develop this syndrome following their cancer diagnosis.In contrast, our case was diagnosed with SPS before the discovery of cancer, underscoring the significance of SPS as a potential early indicator of the underlying cause.However, in our case, the presenting symptoms primarily raised clinical suspicion of malignancy, as the patient was an older adult experiencing fever and weight loss.Furthermore, in this case, despite multiple consultations with infectious disease specialists and oncologists, he only received intravenous antibiotics and corticosteroid treatment without a definitive diagnostic plan to identify the underlying etiology of the symptoms.
The coexistence of SPS and GZL in this case is also notable, given the rarity and diagnostic challenges associated with both conditions.GZL, in particular, is a rare form of lymphoma that presents a diagnostic and clinical dilemma for pathologists due to its complex morphological and phenotypic characteristics.Oncologists also face challenges in managing GZL due to its aggressive nature and the lack of well-established treatment guidelines. 11n conclusion, this case emphasizes the importance of a comprehensive evaluation of patients presenting with SPS to uncover any underlying conditions, even when the symptoms of SPS overshadow other clinical manifestations.This underscores the necessity of a multidisciplinary approach to arrive at a definitive diagnosis.

F I G U R E 1
High-resolution CT (HRCT) of the chest showing hilar lymphadenopathy.F I G U R E 2 Low power view of the core needle biopsy showing small fragment of lymphoid tissue with anthracosis, containing polymphic lymphoid cells.(H&E × 100).F I G U R E 3 High power view of the lymphoid tissue showing many large lymphoid cells resembling Hodgkin cells and Red Sternberg cells.(H&E × 200).F I G U R E 4 Immunohistochemical staining for CD3, showing positive staining in background small lymphocytes and negative staining of large, atypical cells.three times a day, along with Clobazam a daily dose of 10 mg.
et al. in 2009.These criteria encompass both clinical and F I G U R E 5 Immunohistochemical staining for CD30, showing positive staining of large lymphoid cells.F I G U R E 6 Immunohistochemical staining for PAX5, showing positive staining in large, atypical cells.F I G U R E 7Immunohistochemical staining for CD20 which is positive in some background small lymphocytes and large, atypical cells.